Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2839-E2848. doi: 10.1073/pnas.1720662115. Epub 2018 Mar 5.

BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure.

Author information

1
Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; karinag@vet.upenn.edu cideciya@pennmedicine.upenn.edu.
2
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; karinag@vet.upenn.edu cideciya@pennmedicine.upenn.edu.
3
Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
4
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
5
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
6
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
7
Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32611.
8
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 2L3, Canada.

Abstract

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.

KEYWORDS:

AAV BEST1 gene therapy; RPE; bestrophinopathy; microvilli; photoreceptors

PMID:
29507198
PMCID:
PMC5866594
DOI:
10.1073/pnas.1720662115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: W.W.H. and the University of Florida have a financial interest in the use of AAV therapies, and own equity in a company (AGTC, Inc.) that might, in the future, commercialize some aspects of this work.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center